Highly potent, orally active, metabolically stable, long-lived opioid agents for the treatment of alcoholism that have decreased side effects such as nausea, addiction liability, immunosuppression and respiratory depression represents a great unmet need. While a mu opioid receptor antagonist is currently approved by the FDA for alcoholism, it possesses several drawbacks. Recently, human clinical trials have shown that a new class of opioid with an improved side effect profile is available. In this Phase I proposal, efficacious congeners of these novel opioids specifically designed to be antagonists of the mu opioid receptor will be optimized by medicinal chemistry and tested in vitro and in vivo for pharmacological activity. Medicinal chemistry proposed herein for Phase I will lead to additional lead optimization of the most efficacious drug candidates identified previously. The Aims of this proposal include: 1) Test the feasibility of the currently available novel opioid antagonists to decrease alcohol consumption in an animal model, 2) Optimize the pharmacological activity and 3) Maximize the preclinical safety of the most promising drug candidates. After the successful completion of this work, more extensive testing of drug candidate compounds will be done in animals in Phase II. The goal of our feasibility work is to show that efficacious and safe agents can be observed in animal models based on our in vitro data. We expect that development of the proposed novel anti-alcoholism drug candidates will provide new agents useful in the future amelioration of human suffering and economical loss. Anti-alcoholism medication, animal models, drug development, opioid drug evaluation. The need for potent, orally active, metabolically stable, long-lived medication to address alcohol abuse is immense. Procurement of a long-lasting oral anti-alcoholism medication that has an improved side effect profile compared with agents currently in use will provide a therapeutic that is currently not available. The potential commercial application of the work is that the research could lead to a 'blockbuster' drug product. [unreadable] [unreadable]